N-6-aminopurinyl-4-hydroxy-2-methyl-2H-1,2-benxothiazine-3-carboxamide 1,1-dioxide compound
The invention relates to a derivative of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide of the formula: ##STR1## in which X is 6-aminopurinyl. The above compound exhibits anti-inflammatory activity.
The present invention relates to compounds having pharmacological activity.
More precisely, this invention relates to compounds useful in human as well as veterinary therapy for the treatment of various types of inflammatory conditions.
Further, the present invention concerns a process for the preparation of said derivatives.
From U.S. Pat. No. 3,591,584, several benzothiazine dioxides are known. Such compounds have an anti-inflammatory activity and, as they are not steroidal compounds, they are free from the undesired inherent side effects of the steroidal anti-inflammatory compounds.
The derivatives of this invention correspond to the following formula: ##STR2## in which X represents the radical of one of the following compounds: 6-aminopurine, amino-imidazole, amino-oxasole; or of an amino-acid such as glutamic acid, aspartic acid, histidine, lysine and the like.
The compounds of this invention have very good anti-inflammatory properties and are, therefore, useful in the therapy for the treatment of inflammatory states of various origins.
Particularly, the compounds of the present invention are quite suitable for the treatment of rheumatic diseases comprising rheumatoid arthritis, due also to their ability to reduce the swelling which usually accompanies such diseases.
Of all the compounds of this invention, the one now preferred can be represented by the following formula: ##STR3## which can be named N-(6-amminopurinyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide.
The synthesis of compound (V) can be so outlined: treating of sodium saccharinate (I) with methyl chloroacetate produces the methyl ester of 3-oxo-1,2-benzoisothiazoline-2-acetic acid (II), the rearrangement of which in a basic medium provides the methyl ester of 6-oxy-2H-1,2-benzothiazine-3-carboxylic acid (III), from which, by methylating with CH.sub.3 I, compound (IV) is obtained.
Reaction of (IV) with adenine (6-aminopurine) under drastic conditions at a temperature higher than 150.degree. provides (V) with a 20% yield.
The following example aims at better illustrating this invention.
EXAMPLE 1A solution of 4.0 g (0.015 mole) of methyl-4-oxy-2-methyl-2H-1,2 bezothiazine-3-carboxylate 1,1-dioxide and 2.23 g (0.0165 moles) of adenine in 300 ml of anhydrous xylene is refluxed 24 hours in a Soxhlet and in the presence of molecular sieves.
From time to time, a part of the solvent is distilled off and replaced by acid xylene.
The reaction progress is maintained by t.l.c. (CHCl.sub.3 /MeOH 4:1).
After cooling and filtering the suspension, 1.1. g. of compound (V) by repeated crystallizations from MeOH, is obtained.
Yield.about.20%.
FeCl.sub.3 assay for positive (red) enolic OH.
Empirical formula C.sub.15 H.sub.12 N.sub.6 SO.sub.4.
Molecular weight: 373.06.
Melting point: 206.degree.-.degree..
Analysis: C=48.32; H=3.32; N=22.57; S=8.63; O=17.16.
The product is in the powder form, light yellow in color, nearly odourless, and tasteless. It is practically insoluble in H.sub.2 O, little and soluble in ether and chloroform, soluble in methanol and ethanol, particularly when hot.
Mass spectrum: it was obtained on a Varian Mat CH.sub.5 spectrometer by direct introduction at 70 eV.
.sup.1 H NMR Spectrum: it was obtained by Varian T 60. Solvent: DMSO d.sub.6 (I 1.02-2.31;7.10).
IR Spectrum: it was performed by a Perkin Elmer spectrofotometer, Mod. 180: 6.0;6.20; 6.26.mu. (endo form).
Thin layer chromatography: performed on silica gel G plates; (0.25 mm layer); Eluent: CHCl.sub.3 /MeoH 4:1; Rf: 0.5 (average).
Claims
1. A derivative of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide of the formula: ##STR5## in which X represents a radical of 6-aminopurine, amino-imidazole, glutamic acid, aspartic acid, histidine, or lysine.
| RE29836 | November 14, 1978 | Zinnes et al. |
| 3591584 | July 1971 | Lombardino |
| 4289879 | September 15, 1981 | Lombardino |
| 4434163 | February 28, 1984 | Lombardino |
| 0070888 | May 1982 | JPX |
- Ito, Shinichi, C.A., vol. 97, 1982, p. 729, (127648a). Goodman et al., "The Pharmacological Basis of Therapeutics", 6th ed., Macmillian Publ. Co., N.Y., N.Y., 1975, pp. 717, and 720-723.
Type: Grant
Filed: Oct 4, 1983
Date of Patent: Mar 25, 1986
Assignee: Francia Farmaceutici s.r.l.
Inventor: Giorgio A. Francia (Milan)
Primary Examiner: Henry R. Jiles
Assistant Examiner: J. G. Mullins
Law Firm: Ostrolenk, Faber, Gerb & Soffen
Application Number: 6/539,073
International Classification: C07D27902;
